© 2015. Published by The Company of Biologists Ltd | Journal of Cell Science (2015) 00, 1-7 doi:10.1242/jcs.151159

CELL SCIENCE AT A GLANCE

The galectin lattice at a glance Ivan R. Nabi1, *, Jay Shankar1 and James W. Dennis2,*

ABSTRACT Galectins are a family of widely expressed β-galactoside-binding lectins in metazoans. The 15 mammalian galectins have either one or two conserved carbohydrate recognition domains (CRDs), with galectin-3 being able to pentamerize; they form complexes that crosslink glycosylated ligands to form a dynamic lattice. The galectin lattice regulates the diffusion, compartmentalization and endocytosis of plasma membrane glycoproteins and glycolipids. The galectin lattice also regulates the selection, activation and arrest of T cells, receptor kinase signaling and the functionality of membrane receptors, including the glucagon receptor, glucose and amino acid transporters, cadherins and integrins. The affinity of transmembrane glycoproteins to the galectin lattice is proportional to the number and branching of their N-glycans; with branching being mediated by Golgi N-acetylglucosaminyltransferase-

1

Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, 2 Canada V6T 1Z3. Department of Medical Genetics and Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada M5G 1L5.

KEY WORDS: MGATs, Endocytosis, Galectin, Glycolipid, Glycosylation, Receptor

Introduction

Galectins were initially isolated as β-galactoside -binding proteins and, subsequently, characterized as a family of 15 genes in mammals with one or two conserved ∼130 amino-acid-long carbohydrate recognition domains (CRDs) (Cooper, 2002; Drickamer and Fadden, 2002; Seetharaman et al., 1998). Galectins are synthesized in the cytoplasm and interact with cell surface glycans following their secretion by a non-classical exocytic pathway (i.e. not via the ER/ Golgi secretory route), that is likely to be an exosome-mediated secretory route (Hughes, 1999; Jones et al., 2010). The β-galactoside epitopes are di- to tetra-saccharide sequences that are widely found in

Journal of Cell Science

*Authors for correspondence ([email protected], [email protected])

branching enzymes and the supply of UDP-GlcNAc through metabolite flux through the hexosamine biosynthesis pathway. The relative affinities of glycoproteins for the galectin lattice depend on the activities of the Golgi enzymes that generate the epitopes of their ligands and, thus, provide a means to analyze biological function of lectins and of the ‘glycome’ more broadly.

1

JCS Advance Online Article. Posted on 19 June 2015

oligosaccharide modifications (N- and O-glycans) to glycoproteins and glycolipids of vertebrate tissues. The galectins are a subfamily of glycan-binding proteins or ‘lectins’, a designation coined many decades ago for proteins in plants and microbial extracts that display hemagglutin activity (Sharon, 2008). The galectins are: (1) prototypic single-CRD galectins that can form non-covalent homodimers (such as Gal1, Gal2, Gal5, Gal7, Gal10, Gal11, Gal13, Gal14 and Gal15), (2) tandem-repeats of two CRD motifs (Gal4, Gal6, Gal8, Gal9 and Gal12) or, (3) the chimera-type galectin-3 (Gal3) with a single CRD and an intrinsically disordered sequence at the N-terminal domain that promotes oligomerization (see poster). Single-site-binding affinities are generally low (Kd in the micromolar range) (Hirabayashi et al., 2002), but interactions between galectins and glycoproteins are largely multivalent and, therefore, depend on critical glycan concentrations (Dam et al., 2005; Lee and Lee, 2000). In turn, the affinity of glycoproteins for galectins is determined by the number of glycosylation sites (sequence-encoded information) and the glycosyltransferase activities of the Golgi complex that generate the various βgalactoside-binding epitopes present in glycoproteins (Demetriou et al., 2001), Ser/Thr O-linked glycans (Nguyen et al., 2001) and glycolipids (Boscher et al., 2012). The Galβ1,4GlcNAcβ-epitope is widely present in complex, branched N-glycans of transmembrane glycoproteins, which is the main class of ligands for Gal1 and Gal3 (Patnaik et al., 2006). These glycoproteins are central to biological effects of the galectins, as they include cytokine receptors, nutrient transporters and adhesion receptors, which all are crucial sensors of the environment at the cell surface. In this Cell Science at a Glance article and accompanying poster, we review the biophysical nature of the galectin lattice at the cell surface, how N-glycans regulate the glycoprotein composition within the lattice, and provide examples of lattice function in immunity, metabolism and cancer biology. The galectin lattice: a dynamic planar gel-like polymer

Gal1, Gal3 and Gal9 cluster and restrict mobility of cell surface transmembrane glycoproteins (Demetriou et al., 2001; Johswich et al., 2014; Lajoie et al., 2007; Pace et al., 1999). Fluorescence resonance energy transfer revealed the oligomerization of Gal3, induced by cell surface glycoproteins (Nieminen et al., 2007). The galectin oligomers form bridges between glycoproteins, thereby both promoting but also interfering with protein–protein interaction. Homotypic binding through the N-terminus of Gal3 enables the formation of oligomers up to pentamers that contribute to variable geometries of the crosslinked Gal3 lattice; there is an optimal molar ratio of Gal3 to multivalent ligands, and crosslinking can be inhibited by monovalent ligands (Ahmad et al., 2004). Indeed, proteolysis of the N-terminal extension of Gal3 by metalloproteinases results in the formation of Gal3 monomers that interfere with Gal3-dependent oligomerization (Gong et al., 1999; Ochieng et al., 1994). As might be expected, tandem-repeat galectins are often more potent than the prototype, single-CRD galectins in crosslinking glycoproteins and triggering cell responses (Earl et al., 2011). As such, specific galectins might form segregated lattices, or different galectins might cooperate or compete in lattice formation. However, these particular features of the galectins have not been well characterized and remain to be explored. Gal3 oligomerization and crosslinking of its ligand glycoproteins represents a demixing or phase transition from soluble complexes into gel-like polymer lattices or liquid droplets (Ahmad et al., 2004; Li et al., 2012). Mixing experiments with Gal3 and a bivalent N-glycan in vitro have revealed rapid phase transitions at critical molar ratios between Gal3 and ligands (Ahmad et al., 2004); 2

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dynamics are similar to that of phase transitions by adaptor proteins in receptor signaling (Li et al., 2012) or stress-induced RNA-protein granules (Han et al., 2012). N-glycans generally extend away from the protein surface and are flexible due to rotational freedom of the glycosidic bonds (Guttman et al., 2013). Multivalent interactions and a flexible geometry contribute to the intrinsic disorder (i.e. the many microstates) of the lattice. The N-glycans on extracellular domains are often hundreds of Ångstroms above the plasma membrane, where the galectin lattice extends laterally (see poster). The plasma membrane is also compartmentalized by lipid microdomains (or rafts) and the submembranous cytoskeleton into nanoscale compartments (Kusumi et al., 2012). The galectin lattice represents an additional layer of membrane organization that controls diffusion, complex formation and domain interactions in the plasma membrane (Lajoie et al., 2009). Indeed, proteomic analysis of detergent-resistant membranes (DRMs, or rafts) revealed that the galectin lattice blocks the distribution of many glycoproteins, including solute transporters, into DRM fractions (Boscher et al., 2012). In other words, the galectin lattice is a dynamic microdomain assembled as a gel-like polymer that regulates the distribution of glycoproteins at the cell surface. Galectin lattice composition

In vertebrates, ∼30% of the transcriptome is translated in the secretory pathway and most of the proteins are modified on the lumenal side of the membrane by the N-glycosylation pathway. Galectins bind to glycan motifs found on many glycoconjugates at the cell surface and, in this regard, might appear to lack specificity for individual effectors. Indeed, proteomic analyses of Gal3-interacting partners, Mgat5-dependent raft association and LPHA-binding proteins (the higher affinity galectin ligands) indicate binding of many glycoproteins in parallel (Abbott et al., 2008; Boscher et al., 2012; Lakshminarayan et al., 2014). Nonetheless, a systems-based approach has revealed a selective association of transmembrane glycoproteins with the galectin lattice (Lau et al., 2007). Importantly, the relative affinity of transmembrane glycoproteins for the galectin lattice is proportional to their number of Asn-x-Ser/Thr (NxS/T) N-glycan sites (where x can be any amino acid except Pro) and modification through the Golgi N-glycan branching pathway (Lau et al., 2007) (see poster). In addition, these affinities can vary owing to modifications of the branched N-glycan that occur in the trans Golgi. For example the presence of polylactosamine (repeating units of Gal–GlcNAc) enhances the affinity of glycoproteins for Gal3 and other galectins, whereas α2-6-sialylation reduces the affinity for Gal1 (Amano et al., 2003). By considering the relationship between N-glycan number and branching modification we suggested a model for glycoproteingalectin interactions that accounts for the multivalency and additive effects of the branched N-glycans on galectin binding (Dennis and Brewer, 2013; Dennis et al., 2009). Strong selective forces appear to have acted on NxS/T sites during vertebrate evolution in a manner that supports the lattice model (Lau et al., 2007; Williams et al., 2014). More than 97% of N-glycans are attached at the NxS/T motif within mammalian glycoproteins (Zielinska et al., 2010); they are transferred from the glycolipid Glc3Man9GlcNAc2pyrophosphate-dolichol to Asn by the oligosaccharyltransferase complex (OST) (Varki et al., 2009). This N-glycan is a ligand for the ER protein chaperones calnexin and calreticulin, which enhance protein folding efficiency (Deprez et al., 2005). After folding in the ER, most glycoproteins transit the Golgi complex, where the glucose (Glc) and mannose (Man) residues are trimmed by glycosidases –

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CELL SCIENCE AT A GLANCE

CELL SCIENCE AT A GLANCE

Regulation of receptor kinases by the galectin lattice

The N-glycan-branching pathway generates heterogeneity that is distributed over multiple NxS/T sites in glycoproteins; thus, the number of potential glycoforms (i.e. the glycome) can become very large. However, a computational model based on grouping receptor kinase glycoforms owing to their affinity for Gal3 revealed that the glycome has functional implications at the cellular level (Lau et al., 2007). For example, human receptor kinases involved in growth and proliferation (e.g. EGFR) have approximately five times more NxS/ T N-glycosylation sites than receptors that mediate organogenesis, differentiation and cell cycle arrest [e.g. TGF-β receptor (TGFβR)] (see poster). Receptors with five or more glycosylated sites are largely associated with the galectin lattice and their cell surface levels increase only modestly when the supply of UDP-GlcNAc increases (Lau et al., 2007). However, receptors with only one or few glycosylation sites are below the threshold for lattice association; the fraction of receptors associated with the lattice increases in a switch-like manner when the synthesis of tri- and tetra-antennary N-glycans is stimulated by UDP-GlcNAc. For instance, ligand-driven activation of EGFR (with eight N-glycans) – which is involved in growth signaling – stimulates metabolism and UDP-GlcNAc biosynthesis. This leads to the recruitment of TGFβR (with two N-glycans) into the galectin lattice, thereby promoting autocrine TGF-β and/or Smad signaling, resulting in reduced cell proliferation and inducing epithelial-to-mesenchymal transition (EMT) (Lau et al., 2007). Other factors that regulate surface residency of a receptor include the presence of AP1- or AP2-adaptor-binding sites that promote clathrin-mediated endocytosis through clathrin-coated pits. Receptors that have only few NxS/T sites, are expressed at low levels or show rapid turnover at the cell surface and tend to be more dependent on the galectin lattice for their retention at the surface. Furthermore, because a high degree of membrane remodeling occurs in proliferating cells, macrophage and tumor cells, there is greater demand on the lattice in these cells in order to support the appropriate surface retention of receptors and transporters. TGFβRII (Lau et al., 2007), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Mkhikian et al., 2011) and glucagon receptor (Johswich et al., 2014) are examples of receptors with few NxS/T sites that oppose growth signaling and display a marked dependence on UDP-GlcNAc and/or N-glycan branching for their localization to the cell surface (Dennis and Brewer, 2013; Dennis et al., 2009).

Therefore, both genetic inputs, such as the number of NxS/T sites and trafficking motifs, as well as metabolic cues (the availability of UDP-GlcNAc) control the association of receptors with the galectin lattice (see poster). T-cell receptor and the immune response

Gal1 has been ascribed a broad spectrum of functions in immune cells, as well as in cancer (Bacigalupo et al., 2015), and during angiogenesis (Croci et al., 2014) and other processes (Toscano et al., 2011) (see poster). Gal1 binds to the T-cell-surface glycoproteins CD45, CD43, CD71 and CD7, which induces cell death and determines T-cell fate (Nguyen et al., 2001; Stillman et al., 2006). The main ligand for Gal3 on B-cell lymphoma is the phosphatase CD45; whose binding to Gal3 reduces its activity and opposes apoptosis (Clark et al., 2012). In fact, endogenous Gal3-mediated crosslinking of activated T cells was the first description of a galectin lattice that restrained T-cell receptor (TCR) mobility and reduced their sensitivity to antigen. In this context, Mgat5-deficiency weakens the lattice on T cells, resulting in autoimmunity in mice and a predisposition to multiple sclerosis in humans (Demetriou et al., 2001; Mkhikian et al., 2011). Early during immune synapse signaling, the galectin lattice and actin cytoskeleton segregate TCRs to the outside of raft microdomains that contain CD45, which – in turn – regulates Lck activity and the threshold for activation (Chen et al., 2007). Another study has confirmed that the Gal3 lattice negatively regulates the stability of the immune synapse and of TCR sensitivity in mature cytotoxic T cells (Chen et al., 2009). These studies identify the lattice as a key regulator of TCR sensitivity that can be fine-tuned to defend against pathogens while avoiding autoimmunity. In T cells, the proliferative response to antigen is terminated by recruitment of CTLA-4 to the cell surface. A polymorphism in CTLA-4 that reduces the number of its N-glycans from two to only one is associated with increased risk of autoimmune disease (Mkhikian et al., 2011). Human polymorphisms in MGAT1, MGAT5, and interleukins 2 and 7 (IL7 and IL2) have been shown to genetically interact with CTLA-4 polymorphism through their effect on N-glycosylation and result in a higher combined risk of multiple sclerosis (Mkhikian et al., 2011). Experimental autoimmune encephalomyelitis induced in Gal3-deficient mice revealed a complex role for Gal3 in immune function and disease progression (Jiang et al., 2009). Thymic development of T-cell diversity is also dependent on N-glycan branching and provides another example of opposing but cooperative adaptations (i.e. recognition of pathogens versus self antigens). N-glycan branching regulates the variety of TCR-antigen affinities and acts as both a promoter and destabilizer of receptor dynamics (Zhou et al., 2014). Similarly, dichotomy in the effects of lattice dynamics at the molecular level is also observed for cell adhesion and motility (Partridge et al., 2004; Thiemann and Baum, 2011). Metabolism

The galectin lattice also regulates metabolic homeostasis through nutrient transporters (see poster). Mgat4a −/− mice display hypoinsulinemia, hyperglycaemia and excess weight gain on a high-fat diet, whereas Mgat5 −/− mice are resistant to weight gain and display hypoglycemia (Cheung et al., 2007; Ohtsubo et al., 2005). The Mgat4a-generated branched N-glycan on glucose transporter 2 (Glut2; also known as Slc2a2) binds to Gal9, which slows its lateral mobility and endocytosis, thereby increasing the transport of glucose and the secretion of insulin into pancreatic β cells (Ohtsubo et al., 2005). Furthermore, the presence of Mgat53

Journal of Cell Science

including mannosidase 2A (Man2A) – and remodelled by branching N-acetylglucosaminyltransferases, which form an ordered enzyme cascade that comprises Mgat1, Mgat2, Mgat4a/b/c and Mgat5 (Schachter, 1986). Each Mgat enzyme transfers GlcNAc in a specific linkage to N-glycans, followed by the addition of β-linked galactose; therefore, each branch is a potential ligand for galectin (Galβ1,4GlcNAcβ). The affinity of the N-glycans for galectins increases with branching and poly-N-acetyllactosamine extensions (repeating Galβ1,4GlcNAcβ-units) (Hirabayashi et al., 2002; see poster). The branching enzymes reduce the binding affinity for their common substrate UDP-GlcNAc, (∼300-fold), whereby the Michaelis constant (Km) changes from 0.04 to 10 mM, with Mgat4 and Mgat5 operating near and below their Km, making the synthesis of tri- and tetra-antennary glycans highly sensitive to the supply of this metabolite (Lau et al., 2007). Glucose, glutamine and acetyl-CoA supply the hexosamine pathway and biosynthesis of UDP-GlcNAc and N-glycan branching, thereby regulating glycoprotein retention in the galectin lattice (Abdel Rahman et al., 2013; Grigorian et al., 2007).

Journal of Cell Science (2015) 00, 1-7 doi:10.1242/jcs.151159

Journal of Cell Science (2015) 00, 1-7 doi:10.1242/jcs.151159

induced branched N-glycans on the glucagon receptor (GCGR) promotes crosslinking by Gal9, which reduces its lateral mobility and increases responsiveness to glucagon in hepatocytes. Mgat5 expression and UDP-GlcNAc availability cooperate to form a positive-feedback loop that further increases the responsiveness of the receptor to glucagon (Johswich et al., 2014). In cultured HEK293 epithelial cells, inducible expression of Mgat5 has been shown to promote glutamine transport and to rescue cell growth under conditions of low nutrient availability (Abdel Rahman et al., 2015). Upregulation of Glut1 activity through increased N-glycan branching also promotes its surface residency in tumor cells (Kitagawa et al., 1995). Furthermore, the surface residency of Glut4 has also been shown to increase in cells simulated with insulin or UDP-GlcNAc (Haga et al., 2011; Lau et al., 2007). Taken together, UDP-GlcNAc levels appear to act as sensors of metabolism that function through the galectin lattice to adapt the levels and activity of cell surface receptors and solute transporters in response to nutrient conditions (Dennis et al., 2009).

N-cadherin and of the raft marker GM1 ganglioside, as measured by fluorescence recovery after photobleaching (FRAP) (Boscher et al., 2012). In addition, binding of Gal3 to the N-glycans of β1-integrin stimulates integrin activation and endocytosis, as well as integrindependent fibronectin fibrillogenesis and focal adhesion turnover (Furtak et al., 2001; Goetz et al., 2008; Lagana et al., 2006; Lakshminarayan et al., 2014) (see poster). Although the Gal3 lattice competes with Cav1-positive lipid rafts to promote EGFR signaling to ERK1/2 (MAPK3, MAPK1) (Lajoie et al., 2007), Gal3 stimulation of integrin-mediated RhoA signaling, focal adhesion turnover and cell migration is dependent on phosphorylated Cav1 (Cav1-P) (Goetz et al., 2008; Lagana et al., 2006; Shankar et al., 2012). EGF signaling to RhoA – but not to ERK1/2 – and, in turn, cell migration and fibronectin remodeling, requires Gal3–Cav1-Pdependent integrin activation linking Gal3-dependent receptor kinase and integrin signaling (Boscher and Nabi, 2013). The combined effects of the galectin lattice on receptor kinases, cadherins and integrins, therefore, enhance tumor cell motility.

Cancer

Galectin trafficking

Galectins also have a role in cancer progression. For instance, Gal3 was identified as a cancer-cell-associated protein (Raz and Lotan, 1981) and shown to be upregulated in many cancers, where it promotes cell migration and metastasis (Bresalier et al., 1998; Le Marer and Hughes, 1996). Gal8 promotes growth signaling, adhesion and motility in cancer cells (Levy et al., 2003). Furthermore, increased levels of N-glycan branching is closely associated with tumor malignancy (Dennis et al., 1987, 2009). Accordingly, Mgat5 deficiency reduces tumor growth and metastasis in mouse mammary cancer models (Cheung and Dennis, 2007; Granovsky et al., 2000), and sensitivity to stimulation with growth factors (Partridge et al., 2004). Sensitivity to these growth factors could be rescued by either (1) re-expressing Mgat5, (2) inhibition of constitutive endocytosis or, (3) increasing the level of UDP-GlcNAc by supplementation with GlcNAc (Partridge et al., 2004). GlcNAc supplementation restores the galectin lattice by stimulating the catalytic activity of Mgat1, Mgat2 and Mgat4, thereby generating N-acetyllactosamine branches in Mgat5−/− cells that compensate for the lack of Mgat5-generated branched N-glycans. Recruitment of EGFR to the galectin lattice prevents the inhibition of its signaling by the non-glycosylated membrane lipid raft protein caveolin-1 (Cav1), and late-stage growth of Mgat5−/− mammary tumors is rescued by loss of Cav1 (Lajoie et al., 2007) as well as by an acquired dependency on reactive oxygen species (ROS) inhibition of protein phosphatases (Mendelsohn et al., 2007). Other interventions that enhance the expression of Mgat-branching enzymes (Buckhaults et al., 1997) and/or increase UDP-GlcNAc levels might be able to exert similar effects in rescuing the galectin lattice, pointing to a network of pathways that, together, supports the galectin lattice and its functions at the cell surface (Lau and Dennis, 2008) (see poster). The galectin lattice and expression of Mgat5 are associated with EMT in cancer cells (Lajoie et al., 2007; Partridge et al., 2004), and Gal1 has been recently implicated as an inducer of EMT (Bacigalupo et al., 2015). Cell–cell adhesion is primarily mediated by members of the cadherin family – which are also galectin ligands; for instance, murine epithelial (E)-cadherin carries two N-glycans and neuronal (N)-cadherin has seven N-glycan sites. Mgat5-dependent N-glycan branching and expression of Gal3 destabilizes N-cadherin at cell–cell junctions and, so, promotes the motility of mammary epithelial tumor cells (Boscher et al., 2012; Guo et al., 2009, 2003). Gal3 also increased junctional mobility of

A number of galectins (Gal1, Gal3, Gal4, Gal8 and Gal9) exhibit low-affinity interactions with raft-associated glycosphingolipids (GSLs) (Boscher et al., 2011) (see poster). Direct interactions between Gal3 and GSLs induce membrane bending on protein-free giant unilamellar vesicles (GUVs) and raft-dependent endocytosis through clathrin-independent carriers (CLICs) in cells (Lakshminarayan et al., 2014). Intriguingly, binding of pentameric forms of Shiga toxin and SV40 virus targeting GSL also mediate CLIC-dependent endocytosis (Ewers et al., 2010; Römer et al., 2007). Similarly, the pentameric conformation of Gal3, which is induced by high-density glycolipid ligands might have geometric features that promote GSL clustering, membrane bending and raft-dependent endocytosis (Lakshminarayan et al., 2014). Gal3 promotes raft endocytosis of CD44 and integrins (Furtak et al., 2001; Lakshminarayan et al., 2014), as well as Mgat5dependent parvovirus internalization and infection (Garcin et al., 2015). Indeed, host galectins recognize microbial glycans and might play a role in pathogen attachment and invasion by viruses, bacteria, fungi and parasites (Baum et al., 2014). In polarized MDCK cells, Gal3 is endocytosed at the apical membrane following activation of a raft-dependent pathway to recycling endosomes (Schneider et al., 2010; Straube et al., 2013). Internalized Gal3 interaction with glycosylated cargo in apical recycling endosomes sorts glycoproteins to the apical membrane (Delacour et al., 2007; Schneider et al., 2010). Similarly, in the absence of the basolateral sorting adaptor AP-1B, Gal4 promotes transcytosis and apical sorting of the transferrin receptor through apical recycling endosomes (Perez Bay et al., 2014). Gal3, Gal4, Gal7 and Gal9 have all been shown to be determinants of apical sorting, and are required for epithelial morphogenesis and polarity, the development of the apical lumen and ciliogenesis (Delacour et al., 2006, 2008; Mishra et al., 2010; Mo et al., 2012; Rondanino et al., 2011; Stechly et al., 2009; Torkko et al., 2008). Gal3 trafficking, therefore, involves non-classical secretion from the cytoplasm and glycan-dependent raft endocytosis to recycling endosomes, where it and other galectins play roles in post-Golgi sorting (see poster).

4

Conclusions and perspectives

The galectin lattice is a dynamic, extracellular planar gel-like polymer with crosslinking avidities that depend on the glycan profiles of surface-resident glycoproteins and glycolipids. The

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CELL SCIENCE AT A GLANCE

relative affinity of glycoproteins for the galectin lattice varies with the number of binding sites and is conditionally regulated by N-glycan modification/branching due to Golgi enzyme activity and nucleotide–sugar metabolism. This model for galectin function has been validated in autoimmune disease, T-cell development and cancer cell biology. The role of the galectin lattice in autoimmunity illustrates the power of a biological framework or model to help make predictions that can be tested by using genetics and biochemistry experiments (Li et al., 2013; Mkhikian et al., 2011). Although our understanding of galectin lattice organization and structure is taking shape, it is still quite limited. Future studies should develop an understanding of the interplay between multiple galectins at the systems-level, and of the tissue-specific expression patterns of Golgi enzymes as well as glycoconjugates. Gal1 and Gal3 also regulate Ras signaling on the inner leaflet of the plasma membrane as well as mRNA splicing in nuclear ribonucleoprotein complexes – activities that are independent of their CRD-mediated binding to glycans (Haudek et al., 2010; Shalom-Feuerstein et al., 2008). However, like the galectin lattice, these activities may also depend on the multivalent protein–protein adaptor-like functions of these two proteins. The relationship between the extracellular carbohydrate-binding functions of galectins and their intracellular roles is an interesting aspect that will require further studies. Competing interests The authors declare no competing or financial interests.

Funding Work on the galectin lattice in the laboratories of I.R.N. and J.W.D. is supported by a grant from the Canadian Institutes for Health Research [grant number: CIHR MOP126029] and Canadian Cancer Society [grant number: 2010-7000444]. J.S. is the recipient of a Postdoctoral Fellowship from the Canadian Foundation for Breast Cancer (BC/Yukon).

Cell science at a glance A high-resolution version of the poster is available for downloading in the online version of this article at jcs.biologists.org. Individual poster panels are available as JPEG files at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.151159/-/DC1.

References Abbott, K. L., Aoki, K., Lim, J.-M., Porterfield, M., Johnson, R., O’Regan, R. M., Wells, L., Tiemeyer, M. and Pierce, M. (2008). Targeted glycoproteomic identification of biomarkers for human breast carcinoma. J. Proteome Res. 7, 1470-1480. Abdel Rahman, A. M., Ryczko, M., Pawling, J. and Dennis, J. W. (2013). Probing the hexosamine biosynthetic pathway in human tumor cells by multitargeted tandem mass spectrometry. ACS Chem. Biol. 8, 2053-2062. Abdel Rahman, A. M., Ryczko, M., Nakano, M., Pawling, J., Rodrigues, T., Johswich, A., Taniguchi, N. and Dennis, J. W. (2015). Golgi N-glycan branching N-acetylglucosaminyltransferases I, V and VI promote nutrient uptake and metabolism. Glycobiology 25, 225-240. Ahmad, N., Gabius, H.-J., André , S., Kaltner, H., Sabesan, S., Roy, R., Liu, B., Macaluso, F., Brewer, C. F. (2004). Galectin-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes. J. Biol. Chem. 279, 10841-10847. Amano, M., Galvan, M., He, J. and Baum, L. G. (2003). The ST6Gal I sialyltransferase selectively modifies N-glycans on CD45 to negatively regulate galectin-1-induced CD45 clustering, phosphatase modulation, and T cell death. J. Biol. Chem. 278, 7469-7475. Bacigalupo, M. L., Manzi, M., Espelt, M. V., Gentilini, L. D., Compagno, D., Laderach, D. J., Wolfenstein-Todel, C., Rabinovich, G. A. and Troncoso, M. F. (2015). Galectin-1 triggers epithelial-mesenchymal transition in human hepatocellular carcinoma cells. J. Cell Physiol. 230, 1298-1309. Baum, L. G., Garner, O. B., Schaefer, K. and Lee, B. (2014). Microbe–host interactions are positively and negatively regulated by galectin–glycan interactions. Front. Immunol. 5, 284. Boscher, C. and Nabi, I. R. (2013). Galectin-3- and phospho-caveolin-1-dependent outside-in integrin signaling mediates the EGF motogenic response in mammary cancer cells. Mol. Biol. Cell 24, 2134-2145. Boscher, C., Dennis, J. W. and Nabi, I. R. (2011). Glycosylation, galectins and cellular signaling. Curr. Opin. Cell Biol. 23, 383-392.

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Boscher, C., Zheng, Y. Z., Lakshminarayan, R., Johannes, L., Dennis, J. W., Foster, L. J. and Nabi, I. R. (2012). Galectin-3 protein regulates mobility of Ncadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J. Biol. Chem. 287, 32940-32952. Bresalier, R. S., Mazurek, N., Sternberg, L. R., Byrd, J. C., Yunker, C. K., NangiaMakker, P. and Raz, A. (1998). Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3. Gastroenterology 115, 287-296. Buckhaults, P., Chen, L., Fregien, N. and Pierce, M. (1997). Transcriptional regulation of N-acetylglucosaminyltransferase V by the src Oncogene. J. Biol. Chem. 272, 19575-19581. Chen, I.-J., Chen, H.-L. and Demetriou, M. (2007). Lateral compartmentalization of T cell receptor versus CD45 by galectin-N-glycan binding and microfilaments coordinate basal and activation signaling. J. Biol. Chem. 282, 35361-35372. Chen, H.-Y., Fermin, A., Vardhana, S., Weng, I.-C., Lo, K. F. R., Chang, E.-Y., Maverakis, E., Yang, R.-Y., Hsu, D. K., Dustin, M. L. et al. (2009). Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc. Natl. Acad. Sci. USA 106, 14496-14501. Cheung, P. and Dennis, J. W. (2007). Mgat5 and Pten interact to regulate cell growth and polarity. Glycobiology 17, 767-773. Cheung, P., Pawling, J., Partridge, E. A., Sukhu, B., Grynpas, M. and Dennis, J. W. (2007). Metabolic homeostasis and tissue renewal are dependent on beta1,6GlcNAc-branched N-glycans. Glycobiology 17, 828-837. Clark, M. C., Pang, M., Hsu, D. K., Liu, F.-T., de Vos, S., Gascoyne, R. D., Said, J. and Baum, L. G. (2012). Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death. Blood 120, 4635-4644. Cooper, D. N. W. (2002). Galectinomics: finding themes in complexity. Biochim. Biophys. Acta 1572, 209-231. Croci, D. O., Cerliani, J. P., Dalotto-Moreno, T., Mé ndez-Huergo, S. P., Mascanfroni, I. D., Dergan-Dylon, S., Toscano, M. A., Caramelo, J. J., Garcı́a-Vallejo, J. J., Ouyang, J. et al. (2014). Glycosylation-dependent lectinreceptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 156, 744-758. Dam, T. K., Gabius, H.-J., André , S., Kaltner, H., Lensch, M. and Brewer, C. F. (2005). Galectins bind to the multivalent glycoprotein asialofetuin with enhanced affinities and a gradient of decreasing binding constants. Biochemistry 44, 12564-12571. Delacour, D., Cramm-Behrens, C. I., Drobecq, H., Le Bivic, A., Naim, H. Y. and Jacob, R. (2006). Requirement for galectin-3 in apical protein sorting. Curr. Biol. 16, 408-414. Delacour, D., Greb, C., Koch, A., Salomonsson, E., Leffler, H., Le Bivic, A. and Jacob, R. (2007). Apical sorting by galectin-3-dependent glycoprotein clustering. Traffic 8, 379-388. Delacour, D., Koch, A., Ackermann, W., Eude-Le Parco, I., Elsasser, H.-P., Poirier, F. and Jacob, R. (2008). Loss of galectin-3 impairs membrane polarisation of mouse enterocytes in vivo. J. Cell Sci. 121, 458-465. Demetriou, M., Granovsky, M., Quaggin, S. and Dennis, J. W. (2001). Negative regulation of T-cell activation and autoimmunity by Mgat5N-glycosylation. Nature 409, 733-739. Dennis, J. W. and Brewer, C. F. (2013). Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications. Mol. Cell. Proteome. 12, 913-920. Dennis, J. W., Laferte, S., Waghorne, C., Breitman, M. L. and Kerbel, R. S. (1987). Beta 1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236, 582-585. Dennis, J. W., Nabi, I. R. and Demetriou, M. (2009). Metabolism, cell surface organization, and disease. Cell 139, 1229-1241. Deprez, P., Gautschi, M. and Helenius, A. (2005). More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle. Mol. Cell 19, 183-195. Drickamer, K. and Fadden, A. J. (2002). Genomic analysis of C-type lectins. Biochem. Soc. Symp. 69, 59-72. Earl, L. A., Bi, S. and Baum, L. G. (2011). Galectin multimerization and lattice formation are regulated by linker region structure. Glycobiology 21, 6-12. Ewers, H., Rö mer, W., Smith, A. E., Bacia, K., Dmitrieff, S., Chai, W., Mancini, R., Kartenbeck, J., Chambon, V., Berland, L. et al. (2010). GM1 structure determines SV40-induced membrane invagination and infection. Nat. Cell Biol. 12, 11-18; sup pp 1-12. Furtak, V., Hatcher, F. and Ochieng, J. (2001). Galectin-3 mediates the endocytosis of beta-1 integrins by breast carcinoma cells. Biochem. Biophys. Res. Comm. 289, 845-850. Garcin, P. O., Nabi, I. R. and Panté , N. (2015). Galectin-3 plays a role in minute virus of mice infection. Virology 481, 63-72. Goetz, J. G., Joshi, B., Lajoie, P., Strugnell, S. S., Scudamore, T., Kojic, L. D. and Nabi, I. R. (2008). Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine phosphorylated caveolin-1. J. Cell Biol. 180, 1261-1275. Gong, H. C., Honjo, Y., Nangia-Makker, P., Hogan, V., Mazurak, N., Bresalier, R. S. and Raz, A. (1999). The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells. Cancer Res. 59, 6239-6245.

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Journal of Cell Science

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Granovsky, M., Fata, J., Pawling, J., Muller, W. J., Khokha, R. and Dennis, J. W. (2000). Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat. Med. 6, 306-312. Grigorian, A., Lee, S.-U., Tian, W., Chen, I.-J., Gao, G., Mendelsohn, R., Dennis, J. W. and Demetriou, M. (2007). Control of T cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J. Biol. Chem. 282, 20027-20035. Guo, H.-B., Lee, I., Kamar, M. and Pierce, M. (2003). N-acetylglucosaminyltransferase V expression levels regulate cadherin-associated homotypic cell-cell adhesion and intracellular signaling pathways. J. Biol. Chem. 278, 52412-52424. Guo, H.-B., Johnson, H., Randolph, M., Lee, I. and Pierce, M. (2009). Knockdown of GnT-Va expression inhibits ligand-induced downregulation of the epidermal growth factor receptor and intracellular signaling by inhibiting receptor endocytosis. Glycobiology 19, 547-559. Guttman, M., Weinkam, P., Sali, A. and Lee, K. K. (2013). All-atom ensemble modeling to analyze small-angle x-ray scattering of glycosylated proteins. Structure 21, 321-331. Haga, Y., Ishii, K. and Suzuki, T. (2011). N-glycosylation is critical for the stability and intracellular trafficking of glucose transporter GLUT4. J. Biol. Chem. 286, 31320-31327. Han, T. W., Kato, M., Xie, S., Wu, L. C., Mirzaei, H., Pei, J., Chen, M., Xie, Y., Allen, J., Xiao, G. et al. (2012). Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768-779. Haudek, K. C., Patterson, R. J. and Wang, J. L. (2010). SR proteins and galectins: what’s in a name? Glycobiology 20, 1199-1207. Hirabayashi, J., Hashidate, T., Arata, Y., Nishi, N., Nakamura, T., Hirashima, M., Urashima, T., Oka, T., Futai, M., Muller, W. E. G. et al. (2002). Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim. Biophys. Acta 1572, 232-254. Hughes, R. C. (1999). Secretion of the galectin family of mammalian carbohydratebinding proteins. Biochim. Biophys. Acta 1473, 172-185. Jiang, H.-R., Al Rasebi, Z., Mensah-Brown, E., Shahin, A., Xu, D., Goodyear, C. S., Fukada, S. Y., Liu, F.-T., Liew, F. Y. and Lukic, M. L. (2009). Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J. Immunol. 182, 1167-1173. Johswich, A., Longuet, C., Pawling, J., Rahman, A. A., Ryczko, M., Drucker, D. J. and Dennis, J. W. (2014). N-glycan remodeling on glucagon receptor is an effector of nutrient sensing by the hexosamine biosynthesis pathway. J. Biol. Chem. 289, 15927-15941. Jones, J. L., Saraswati, S., Block, A. S., Lichti, C. F., Mahadevan, M. and Diekman, A. B. (2010). Galectin-3 is associated with prostasomes in human semen. Glycoconj. J. 27, 227-236. Kitagawa, T., Tsuruhara, Y., Hayashi, M., Endo, T. and Stanbridge, E. J. (1995). A tumor-associated glycosylation change in the glucose transporter GLUT1 controlled by tumor suppressor function in human cell hybrids. J. Cell Sci. 108, 3735-3743. Kusumi, A., Fujiwara, T. K., Morone, N., Yoshida, K. J., Chadda, R., Xie, M., Kasai, R. S. and Suzuki, K. G. N. (2012). Membrane mechanisms for signal transduction: the coupling of the meso-scale raft domains to membrane-skeleton-induced compartments and dynamic protein complexes. Semin. Cell Dev. Biol. 23, 126-144. Lagana, A., Goetz, J. G., Cheung, P., Raz, A., Dennis, J. W. and Nabi, I. R. (2006). Galectin binding to Mgat5-modified N-glycans regulates fibronectin matrix remodeling in tumor cells. Mol. Cell. Biol. 26, 3181-3193. Lajoie, P., Partridge, E. A., Guay, G., Goetz, J. G., Pawling, J., Lagana, A., Joshi, B., Dennis, J. W. and Nabi, I. R. (2007). Plasma membrane domain organization regulates EGFR signaling in tumor cells. J. Cell Biol. 179, 341-356. Lajoie, P., Goetz, J. G., Dennis, J. W. and Nabi, I. R. (2009). Lattices, rafts, and scaffolds: domain regulation of receptor signaling at the plasma membrane. J. Cell Biol. 185, 381-385. Lakshminarayan, R., Wunder, C., Becken, U., Howes, M. T., Benzing, C., Arumugam, S., Sales, S., Ariotti, N., Chambon, V., Lamaze, C. et al. (2014). Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrinindependent carriers. Nat. Cell Biol. 16, 595-606. Lau, K. S. and Dennis, J. W. (2008). N-Glycans in cancer progression. Glycobiology 18, 750-760. Lau, K. S., Partridge, E. A., Grigorian, A., Silvescu, C. I., Reinhold, V. N., Demetriou, M. and Dennis, J. W. (2007). Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123-134. Le Marer, N. and Hughes, R. C. (1996). Effects of the carbohydrate-binding protein galectin-3 on the invasiveness of human breast carcinoma cells. J. Cell. Physiol. 168, 51-58. Lee, R. T. and Lee, Y. C. (2000). Affinity enhancement by multivalent lectin– carbohydrate interaction. Glycoconj. J. 17, 543-551. Levy, Y., Ronen, D., Bershadsky, A. D. and Zick, Y. (2003). Sustained induction of ERK, protein kinase B, and p70 S6 kinase regulates cell spreading and formation of F-actin microspikes upon ligation of integrins by galectin-8, a mammalian lectin. J. Biol. Chem. 278, 14533-14542. Li, P., Banjade, S., Cheng, H.-C., Kim, S., Chen, B., Guo, L., Llaguno, M., Hollingsworth, J. V., King, D. S., Banani, S. F. et al. (2012). Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336-340.

6

Journal of Cell Science (2015) 00, 1-7 doi:10.1242/jcs.151159

Li, C. F., Zhou, R. W., Mkhikian, H., Newton, B. L., Yu, Z. and Demetriou, M. (2013). Hypomorphic MGAT5 polymorphisms promote multiple sclerosis cooperatively with MGAT1 and interleukin-2 and 7 receptor variants. J. Neuroimmunol. 256, 71-76. Mendelsohn, R., Cheung, P., Berger, L., Partridge, E., Lau, K., Datti, A., Pawling, J. and Dennis, J. W. (2007). Complex N-glycan and metabolic control in tumor cells. Cancer Res. 67, 9771-9780. Mishra, R., Grzybek, M., Niki, T., Hirashima, M. and Simons, K. (2010). Galectin9 trafficking regulates apical-basal polarity in Madin-Darby canine kidney epithelial cells. Proc. Natl. Acad. Sci. USA 107, 17633-17638. Mkhikian, H., Grigorian, A., Li, C. F., Chen, H.-L., Newton, B., Zhou, R. W., Beeton, C., Torossian, S., Tatarian, G. G., Lee, S.-U. et al. (2011). Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nat. Commun. 2, 334. Mo, D., Costa, S. A., Ihrke, G., Youker, R. T., Pastor-Soler, N., Hughey, R. P. and Weisz, O. A. (2012). Sialylation of N-linked glycans mediates apical delivery of endolyn in MDCK cells via a galectin-9-dependent mechanism. Mol. Biol. Cell 23, 3636-3646. Nguyen, J. T., Evans, D. P., Galvan, M., Pace, K. E., Leitenberg, D., Bui, T. N. and Baum, L. G. (2001). CD45 modulates galectin-1-induced T cell death: regulation by expression of core 2 O-glycans. J. Immunol. 167, 5697-5707. Nieminen, J., Kuno, A., Hirabayashi, J. and Sato, S. (2007). Visualization of galectin-3 oligomerization on the surface of neutrophils and endothelial cells using fluorescence resonance energy transfer. J. Biol. Chem. 282, 1374-1383. Ochieng, J., Fridman, R., Nangia-Makker, P., Kleiner, D. E., Liotta, L. A., StetlerStevenson, W. G. and Raz, A. (1994). Galectin-3 is a novel substrate for human matrix metalloproteinases-2 and -9. Biochemistry 33, 14109-14114. Ohtsubo, K., Takamatsu, S., Minowa, M. T., Yoshida, A., Takeuchi, M. and Marth, J. D. (2005). Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123, 1307-1321. Pace, K. E., Lee, C., Stewart, P. L. and Baum, L. G. (1999). Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1. J. Immunol. 163, 3801-3811. Partridge, E. A., Le Roy, C., Di Guglielmo, G. M., Pawling, J., Cheung, P., Granovsky, M., Nabi, I. R., Wrana, J. L. and Dennis, J. W. (2004). Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306, 120-124. Patnaik, S. K., Potvin, B., Carlsson, S., Sturm, D., Leffler, H. and Stanley, P. (2006). Complex N-glycans are the major ligands for galectin-1, -3, and -8 on Chinese hamster ovary cells. Glycobiology 16, 305-317. Perez Bay, A. E., Schreiner, R., Benedicto, I. and Rodriguez-Boulan, E. J. (2014). Galectin-4-mediated transcytosis of transferrin receptor. J. Cell Sci. 127, 4457-4469. Raz, A. and Lotan, R. (1981). Lectin-like activities associated with human and murine neoplastic cells. Cancer Res. 41, 3642-3647. Rö mer, W., Berland, L., Chambon, V., Gaus, K., Windschiegl, B., Tenza, D., Aly, M. R. E., Fraisier, V., Florent, J.-C., Perrais, D. et al. (2007). Shiga toxin induces tubular membrane invaginations for its uptake into cells. Nature 450, 670-675. Rondanino, C., Poland, P. A., Kinlough, C. L., Li, H., Rbaibi, Y., Myerburg, M. M., Al-bataineh, M. M., Kashlan, O. B., Pastor-Soler, N. M., Hallows, K. R. et al. (2011). Galectin-7 modulates the length of the primary cilia and wound repair in polarized kidney epithelial cells. Am. J. Physiol. Renal Physiol. 301, F622-F633. Schachter, H. (1986). Biosynthetic controls that determine the branching and microheterogeneity of protein-bound oligosaccharides. Biochem. Cell Biol. 64, 163-181. Schneider, D., Greb, C., Koch, A., Straube, T., Elli, A., Delacour, D. and Jacob, R. (2010). Trafficking of galectin-3 through endosomal organelles of polarized and non-polarized cells. Eur. J. Cell Biol. 89, 788-798. Seetharaman, J., Kanigsberg, A., Slaaby, R., Leffler, H., Barondes, S. H. and Rini, J. M. (1998). X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-A resolution. J. Biol. Chem. 273, 13047-13052. Shalom-Feuerstein, R., Plowman, S. J., Rotblat, B., Ariotti, N., Tian, T., Hancock, J. F. and Kloog, Y. (2008). K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. Cancer Res. 68, 6608-6616. Shankar, J., Wiseman, S. M., Meng, F., Kasaian, K., Strugnell, S., Mofid, A., Gown, A., Jones, S. J. and Nabi, I. R. (2012). Coordinate expression of galectin3 and caveolin-1 in thyroid cancer. J. Pathol. 228, 56-66. Sharon, N. (2008). Lectins: past, present and future. Biochem. Soc. Trans. 36, 1457-1460. Stechly, L., Morelle, W., Dessein, A.-F., André , S., Grard, G., Trinel, D., Dejonghe, M.-J., Leteurtre, E., Drobecq, H., Trugnan, G. et al. (2009). Galectin4-regulated delivery of glycoproteins to the brush border membrane of enterocytelike cells. Traffic 10, 438-450. Stillman, B. N., Hsu, D. K., Pang, M., Brewer, C. F., Johnson, P., Liu, F.-T. and Baum, L. G. (2006). Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J. Immunol. 176, 778-789.

Journal of Cell Science

CELL SCIENCE AT A GLANCE

Straube, T., von Mach, T., Hö nig, E., Greb, C., Schneider, D. and Jacob, R. (2013). pH-dependent recycling of galectin-3 at the apical membrane of epithelial cells. Traffic 14, 1014-1027. Thiemann, S. and Baum, L. G. (2011). The road less traveled: regulation of leukocyte migration across vascular and lymphatic endothelium by galectins. J. Clin. Immunol. 31, 2-9. Torkko, J. M., Manninen, A., Schuck, S. and Simons, K. (2008). Depletion of apical transport proteins perturbs epithelial cyst formation and ciliogenesis. J. Cell Sci. 121, 1193-1203. Toscano, M. A., Campagna, L., Molinero, L. L., Cerliani, J. P., Croci, D. O., Ilarregui, J. M., Fuertes, M. B., Nojek, I. M., Fededa, J. P., Zwirner, N. W. et al. (2011). Nuclear factor (NF)-kappaB controls expression of the immunoregulatory glycan-binding protein galectin-1. Mol. Immunol. 48, 1940-1949.

Journal of Cell Science (2015) 00, 1-7 doi:10.1242/jcs.151159

Varki, A., Cummings, R. D., Esko, J., Freeze, H., Stanley, P., Bertozzi, C., Hart, G. W. and Etzler, M. E. (2009). Essentials of Glycobiology. New York: Cold Spring Harbor Laboratory. Williams, R., Ma, X., Schott, R. K., Mohammad, N., Ho, C. Y., Li, C. F., Chang, B. S. W., Demetriou, M. and Dennis, J. W. (2014). Encoding asymmetry of the N-glycosylation motif facilitates glycoprotein evolution. PLoS ONE 9, e86088. Zhou, R. W., Mkhikian, H., Grigorian, A., Hong, A., Chen, D., Arakelyan, A. and Demetriou, M. (2014). N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca(2)(+) signaling. Nat. Immunol. 15, 1038-1045. Zielinska, D. F., Gnad, F., Wiś niewski, J. R. and Mann, M. (2010). Precision mapping of an in vivo N-glycoproteome reveals rigid topological and sequence constraints. Cell 141, 897-907.

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The galectin lattice at a glance.

Galectins are a family of widely expressed β-galactoside-binding lectins in metazoans. The 15 mammalian galectins have either one or two conserved car...
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